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Extreme retinal remodeling triggered by light damage: implications for age related macular degeneration.

Marc RE, Jones BW, Watt CB, Vazquez-Chona F, Vaughan DK, Organisciak DT - Mol. Vis. (2008)

Bottom Line: Across these zones, Müller cells manifest extreme changes in the definitive Müller cell tauQE signature, as well as CRALBP and arginine signals.If focal remodeling in LIRD accurately profiles late stage atrophic age-related macular degenerations, it augurs poorly for simple molecular interventions.Indeed, the LIRD profile in the SD rat manifests more similarities to advanced human atrophic AMD than most genetically or immunologically induced murine models of AMD.

View Article: PubMed Central - PubMed

Affiliation: Ophthalmology, University of Utah, John A. Moran Eye Center, Salt Lake City, UT 84132, USA. robert.marc@hsc.utah.edu

ABSTRACT

Purpose: Our objective was to comprehensively assess the nature and chronology of neural remodeling in retinal degenerations triggered by light-induced retinal damage (LIRD) in adult albino rodents. Our primary hypothesis is that all complete photoreceptor degenerations devolve to extensive remodeling. An hypothesis emergent from data analysis is that the LIRD model closely mimics late-stage atrophic age relared macular degeneration (AMD).

Methods: Sprague-Dawley (SD) rats received intense light exposures of varied durations and survival times ranging from 0 to 240 days. Remodeling was visualized by computational molecular phenotyping (CMP) of a small molecule library: 4-aminobutyrate (gamma), arginine (R), aspartate (D), glutamate (E), glutamine (Q), glutathione (J), glycine (G), and taurine (tau). This library was augmented by probes for key proteins such as rod opsin, cone opsin and cellular retinal binding protein (CRALBP). Quantitative CMP was used to profile 160 eyes from 86 animals in over 6,000 sections.

Results: The onset of remodeling in LIRD retinas is rapid, with immediate signs of metabolic stress in photoreceptors, the retinal pigmented epithelium (RPE), the choriocapillaris, and Müller cells. In particular, anomalous elevated aspartate levels appear to be an early stress marker in photoreceptors. After the stress phase, LIRD progresses to focal photoreceptor degeneration within 14 days and extensive remodeling by 60 days. RPE and choriocapillaris losses parallel Müller cell distal seal formation, with progressive neuronal migration, microneuroma evolution, fluid channel formation, and slow neuronal death. The remaining retina in advanced light damage can be classified as survivor, light damage (LD), or decimated zones where massive Müller cell and neuronal emigration into the choroid leaves a retina depleted of neurons and Müller cells. These zones and their transitions closely resemble human geographic atrophy. Across these zones, Müller cells manifest extreme changes in the definitive Müller cell tauQE signature, as well as CRALBP and arginine signals.

Conclusions: LIRD retinas manifest remodeling patterns of genetic retinal degeneration models, but involve no developmental complexities, and are ultimately more aggressive, devastating the remaining neural retina. The decimation of the neural retina via cell emigration through the perforated retina-choroid interface is a serious denouement. If focal remodeling in LIRD accurately profiles late stage atrophic age-related macular degenerations, it augurs poorly for simple molecular interventions. Indeed, the LIRD profile in the SD rat manifests more similarities to advanced human atrophic AMD than most genetically or immunologically induced murine models of AMD.

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Related in: MedlinePlus

Altered molecular signatures immediately after 48 h of light exposure. Visualization: Quantitative gray-scale images displayed as intensity in mirror-image pairs (AB, CD, EF, GH). Up arrows, choroid-retinal pigment epithelium (RPE) interface; down arrows, Müller cell (MC) end feet; oblique arrows mark the border of the outer nuclear and outer plexiform layers. Scale: All panels are 0.187 mm wide. A: Glutamine signatures are elevated in MCs, with hypertrophy of distal MC processes at the external limiting membrane (box). The RPE layer is severely damaged, with only a few distinct cells (oval). B: Massive taurine depletion in MCs (down arrows) and abnormal elevation in photoreceptors (oval) and bipolar cells. C: 1D4 rod opsin reveals extreme disorganization of rod outer segments and extensive mislocalization of rod opsin into rod somas. D: Glutathione signatures highlight the disorganization of MC processes in the outer retina. E: Aspartate signals are abnormally high in rod inner segments. F: Glutamate signals in particular are abnormally elevated in MCs. G, H: Glycine and γ-aminobutyric acid (GABA) signals seem essentially normal, with no evidence of ischemia or excitotoxicity. Sample metadata: SD Rat, age at LX 60 d, animal #P60–1L-48, left eye, 48 h LX, harvested at 0 days pLX, bloc code 6464, slide code 3548b.
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f4: Altered molecular signatures immediately after 48 h of light exposure. Visualization: Quantitative gray-scale images displayed as intensity in mirror-image pairs (AB, CD, EF, GH). Up arrows, choroid-retinal pigment epithelium (RPE) interface; down arrows, Müller cell (MC) end feet; oblique arrows mark the border of the outer nuclear and outer plexiform layers. Scale: All panels are 0.187 mm wide. A: Glutamine signatures are elevated in MCs, with hypertrophy of distal MC processes at the external limiting membrane (box). The RPE layer is severely damaged, with only a few distinct cells (oval). B: Massive taurine depletion in MCs (down arrows) and abnormal elevation in photoreceptors (oval) and bipolar cells. C: 1D4 rod opsin reveals extreme disorganization of rod outer segments and extensive mislocalization of rod opsin into rod somas. D: Glutathione signatures highlight the disorganization of MC processes in the outer retina. E: Aspartate signals are abnormally high in rod inner segments. F: Glutamate signals in particular are abnormally elevated in MCs. G, H: Glycine and γ-aminobutyric acid (GABA) signals seem essentially normal, with no evidence of ischemia or excitotoxicity. Sample metadata: SD Rat, age at LX 60 d, animal #P60–1L-48, left eye, 48 h LX, harvested at 0 days pLX, bloc code 6464, slide code 3548b.

Mentions: SD rats manifest photoreceptor, Müller cell and RPE stress immediately after light exposure. Stress signals are metabolomic and proteomic (Figure 4 and Figure 5). Rod outer segments are severely disrupted and elevated glutamine, glutathione, and glutamate signals are found in the swollen distal processes of Müller cells at the external limiting membrane. At the same time, taurine levels are severely depressed. The structural damage to photoreceptors is accompanied by mislocalization of rod opsin to inner segments (compare Figure 2G and Figure 3B with Figure 4C and Figure 5B). We have identified several new markers of photoreceptor metabolic stress but here address only the anomalous elevation of L-aspartate in rods of pLX 0 and 14 animals (Figure 4 and Figure 5). As far as we can discern, aspartate “stress” is nearly panretinal at pLX 0 but resolves to a ring of scattered remnant stressed photoreceptors at the LIRD margin by day 60, and slowly disappears. The mislocalization of opsins follows the same pattern: first panretinal, then circumferential to the LIRD focus, and then largely, but not completely absent.


Extreme retinal remodeling triggered by light damage: implications for age related macular degeneration.

Marc RE, Jones BW, Watt CB, Vazquez-Chona F, Vaughan DK, Organisciak DT - Mol. Vis. (2008)

Altered molecular signatures immediately after 48 h of light exposure. Visualization: Quantitative gray-scale images displayed as intensity in mirror-image pairs (AB, CD, EF, GH). Up arrows, choroid-retinal pigment epithelium (RPE) interface; down arrows, Müller cell (MC) end feet; oblique arrows mark the border of the outer nuclear and outer plexiform layers. Scale: All panels are 0.187 mm wide. A: Glutamine signatures are elevated in MCs, with hypertrophy of distal MC processes at the external limiting membrane (box). The RPE layer is severely damaged, with only a few distinct cells (oval). B: Massive taurine depletion in MCs (down arrows) and abnormal elevation in photoreceptors (oval) and bipolar cells. C: 1D4 rod opsin reveals extreme disorganization of rod outer segments and extensive mislocalization of rod opsin into rod somas. D: Glutathione signatures highlight the disorganization of MC processes in the outer retina. E: Aspartate signals are abnormally high in rod inner segments. F: Glutamate signals in particular are abnormally elevated in MCs. G, H: Glycine and γ-aminobutyric acid (GABA) signals seem essentially normal, with no evidence of ischemia or excitotoxicity. Sample metadata: SD Rat, age at LX 60 d, animal #P60–1L-48, left eye, 48 h LX, harvested at 0 days pLX, bloc code 6464, slide code 3548b.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2375357&req=5

f4: Altered molecular signatures immediately after 48 h of light exposure. Visualization: Quantitative gray-scale images displayed as intensity in mirror-image pairs (AB, CD, EF, GH). Up arrows, choroid-retinal pigment epithelium (RPE) interface; down arrows, Müller cell (MC) end feet; oblique arrows mark the border of the outer nuclear and outer plexiform layers. Scale: All panels are 0.187 mm wide. A: Glutamine signatures are elevated in MCs, with hypertrophy of distal MC processes at the external limiting membrane (box). The RPE layer is severely damaged, with only a few distinct cells (oval). B: Massive taurine depletion in MCs (down arrows) and abnormal elevation in photoreceptors (oval) and bipolar cells. C: 1D4 rod opsin reveals extreme disorganization of rod outer segments and extensive mislocalization of rod opsin into rod somas. D: Glutathione signatures highlight the disorganization of MC processes in the outer retina. E: Aspartate signals are abnormally high in rod inner segments. F: Glutamate signals in particular are abnormally elevated in MCs. G, H: Glycine and γ-aminobutyric acid (GABA) signals seem essentially normal, with no evidence of ischemia or excitotoxicity. Sample metadata: SD Rat, age at LX 60 d, animal #P60–1L-48, left eye, 48 h LX, harvested at 0 days pLX, bloc code 6464, slide code 3548b.
Mentions: SD rats manifest photoreceptor, Müller cell and RPE stress immediately after light exposure. Stress signals are metabolomic and proteomic (Figure 4 and Figure 5). Rod outer segments are severely disrupted and elevated glutamine, glutathione, and glutamate signals are found in the swollen distal processes of Müller cells at the external limiting membrane. At the same time, taurine levels are severely depressed. The structural damage to photoreceptors is accompanied by mislocalization of rod opsin to inner segments (compare Figure 2G and Figure 3B with Figure 4C and Figure 5B). We have identified several new markers of photoreceptor metabolic stress but here address only the anomalous elevation of L-aspartate in rods of pLX 0 and 14 animals (Figure 4 and Figure 5). As far as we can discern, aspartate “stress” is nearly panretinal at pLX 0 but resolves to a ring of scattered remnant stressed photoreceptors at the LIRD margin by day 60, and slowly disappears. The mislocalization of opsins follows the same pattern: first panretinal, then circumferential to the LIRD focus, and then largely, but not completely absent.

Bottom Line: Across these zones, Müller cells manifest extreme changes in the definitive Müller cell tauQE signature, as well as CRALBP and arginine signals.If focal remodeling in LIRD accurately profiles late stage atrophic age-related macular degenerations, it augurs poorly for simple molecular interventions.Indeed, the LIRD profile in the SD rat manifests more similarities to advanced human atrophic AMD than most genetically or immunologically induced murine models of AMD.

View Article: PubMed Central - PubMed

Affiliation: Ophthalmology, University of Utah, John A. Moran Eye Center, Salt Lake City, UT 84132, USA. robert.marc@hsc.utah.edu

ABSTRACT

Purpose: Our objective was to comprehensively assess the nature and chronology of neural remodeling in retinal degenerations triggered by light-induced retinal damage (LIRD) in adult albino rodents. Our primary hypothesis is that all complete photoreceptor degenerations devolve to extensive remodeling. An hypothesis emergent from data analysis is that the LIRD model closely mimics late-stage atrophic age relared macular degeneration (AMD).

Methods: Sprague-Dawley (SD) rats received intense light exposures of varied durations and survival times ranging from 0 to 240 days. Remodeling was visualized by computational molecular phenotyping (CMP) of a small molecule library: 4-aminobutyrate (gamma), arginine (R), aspartate (D), glutamate (E), glutamine (Q), glutathione (J), glycine (G), and taurine (tau). This library was augmented by probes for key proteins such as rod opsin, cone opsin and cellular retinal binding protein (CRALBP). Quantitative CMP was used to profile 160 eyes from 86 animals in over 6,000 sections.

Results: The onset of remodeling in LIRD retinas is rapid, with immediate signs of metabolic stress in photoreceptors, the retinal pigmented epithelium (RPE), the choriocapillaris, and Müller cells. In particular, anomalous elevated aspartate levels appear to be an early stress marker in photoreceptors. After the stress phase, LIRD progresses to focal photoreceptor degeneration within 14 days and extensive remodeling by 60 days. RPE and choriocapillaris losses parallel Müller cell distal seal formation, with progressive neuronal migration, microneuroma evolution, fluid channel formation, and slow neuronal death. The remaining retina in advanced light damage can be classified as survivor, light damage (LD), or decimated zones where massive Müller cell and neuronal emigration into the choroid leaves a retina depleted of neurons and Müller cells. These zones and their transitions closely resemble human geographic atrophy. Across these zones, Müller cells manifest extreme changes in the definitive Müller cell tauQE signature, as well as CRALBP and arginine signals.

Conclusions: LIRD retinas manifest remodeling patterns of genetic retinal degeneration models, but involve no developmental complexities, and are ultimately more aggressive, devastating the remaining neural retina. The decimation of the neural retina via cell emigration through the perforated retina-choroid interface is a serious denouement. If focal remodeling in LIRD accurately profiles late stage atrophic age-related macular degenerations, it augurs poorly for simple molecular interventions. Indeed, the LIRD profile in the SD rat manifests more similarities to advanced human atrophic AMD than most genetically or immunologically induced murine models of AMD.

Show MeSH
Related in: MedlinePlus